What Causes Long-COVID?

This modified excerpt from Version 8 of my COVID Guide is a review of the science that will be useful to anyone trying to understand the causes of long-COVID.

Nov 14, 2022

This post is for educational purposes only and is not a form of, or a substitute for, medical or health care advice of any kind.

I am done with my work on COVID, at least until I finish my Vitamins and Minerals 101 Book, so I am now making my scientific review on the likely causes of long-COVID public, just as I did for my work on COVID vaccine side effects.

This is an excerpt of pages 33-45 of my COVID Guide guide (free to Masterpass members here) and contains 48 of the Guide’s 283 references. It does not contain the protocol, but rather the scientific review used to judge the mechanisms most likely underlying the illness. Since I am no longer working on this, I hope it proves useful to anyone doing further work on the topic. This was originally published on August 1, 2022.

What Causes Long-COVID?

Long-COVID, which goes by various names such as “COVID longhauler syndrome” or “post-acute sequelae of COVID-19” refers to signs and symptoms that newly arise or persist after 4 weeks from infection. Definitions vary, and some call for distinguishing between “ongoing symptomatic COVID” from 4-12 weeks and “post-COVID-19 syndrome” from 12 weeks onward. [1] Due to the variability in definitions, estimates of how common long-COVID is are extremely variable, ranging from 10-87% of COVID cases. [2]

Postviral dysfunction is not unique to COVID. It is just getting much more attention than it has from other viruses. Lasting lung dysfunction follows other coronaviruses and flu viruses; allergies and asthma often follow respiratory syncytial virus and rhinoviruses; diverse forms of pneumonia and acute respiratory distress have led to later neurocognitive deficits; and influenza has been implicated in a worsened risk of autoimmune disorders, heart disease, and stroke. [3] Upper respiratory viruses have also broadly been implicated in post-viral disorders of taste and smell. [4]

Most studies of long-COVID are limited by a lack of comparison to the person’s pre-COVID state of health, and this is especially true for studies using tests that are not commonly administered, such as cardiac magnetic resonance imaging (MRI) or cognitive assessment. In a meta-analysis that limited its scope to studies that followed patients from their acute experience with COVID onward, the most common symptoms of long-COVID were fatigue (37%), dyspnea (trouble breathing, 21%), loss of smell (17%) or taste (10%), myalgia (muscle pain, 12%), cough (11%), headache (7%), diarrhea (5%), and chest pain (3%). [1] Meta-analyses casting a wider net have come up with higher estimates for the frequency of these problems and added to them attention deficit (27%) and hair loss (25%) from among an even longer list. [5]

The only risk factors for developing long-COVID that are replicated in many studies and hold up robustly in meta-analysis are the severity of the initial COVID illness and female sex. [6] The association with female sex is the strongest and most consistent risk factor, over and above initial disease severity, but it may be confounded by survivorship bias since men are more likely to die from COVID.

The three leading hypotheses to explain long-COVID are microclots, persistent antigen, and immune dysfunction.

Before we tackle these, however, we must look at two nutritional elephants standing in the room: iron and zinc.

Nutritional Elephants in the Room: Iron and Zinc

Iron

COVID [7] affects iron metabolism similar to sepsis. [8] If the COVID virus enters the blood – as occurs in 44% of those on a ventilator, 27% of those who are merely hospitalized, 13% of those who are diagnosed but not hospitalized, [9] and probably rarely in those infected but not diagnosed – it can attack red blood cells, destroy hemoglobin, and release free heme and iron into circulation. In the post-acute phase, this iron will be sequestered into ferritin so long as the capacity to raise ferritin sufficiently remains intact.

However, the general effect of virtually all inflammation is to shut down iron absorption from food and shuttle circulating or cellular iron into ferritin. This is because some pathogens feed on iron, and shuttling the iron into ferritin prevents them from accessing it. Unfortunately, this also prevents iron from being used by the bone marrow to make red blood cells and leads to anemia of chronic disease. This is a genuine anemia, reflects genuine iron deficiency in the bone marrow, mimics dietary iron deficiency, and departs from the presentation of dietary iron deficiency only in the dramatic elevation of ferritin.

Textbook explanations of iron deficiency anemia [10] reveal fatigue and dyspnea on exertion as the most common symptoms. Iron deficiency anemia is ten times more common in women than men, because women lose iron during menstruation. This means women go into COVID with lower iron stores and would be more likely to develop anemia of chronic disease as a result. This could easily explain female sex as the most robust risk factor for long-COVID.

Iron deficiency also causes cognitive impairment [11] and hair loss. [12,13] In children, it has been shown to cause longer-lasting respiratory infections [14] and is associated with attention deficit. [15] Given that iron deficiency leads to longer-lasting respiratory infections, it is tempting to speculate functional iron deficiency could even explain the persistence of cough.

A study of 75 patients with new-onset fatigue after hospitalization for COVID suggests that anemia of chronic disease is common in long-COVID. [16] Subjects were only included if they had normal oxygen saturation, normal lung function, no other diagnoses that could explain their fatigue, and objective measures of muscle weakness. All of them had elevated ferritin, with the mean just under 500 ng/mL, and 87% of them had low hemoglobin, with the mean for men (11.5 g/dL) 18% below the bottom of the normal range (14-18 g/dL) and the mean for women (10.9 g/dL) 9% below the bottom of the normal range (12-16 g/dL).

The mean ferritin in the foregoing study was similar to an earlier study that compared those with post-COVID fatigue to those who recovered from COVID without enduring symptoms. [17] The group with fatigue had 3.3-fold higher ferritin levels (406 ng/mL vs 124 ng/mL) and every 1 ng/mL increase in serum ferritin was associated with an 0.6% increase in the risk of post-COVID fatigue.

Anemia of chronic disease might be driving the mitochondrial dysfunction that has been observed in some studies.

In a sample of 50 patients with long-COVID referred to a pulmonary physiology laboratory, all patients without preexisting comorbidities had normal lung function, while all 50 patients regardless of their comorbidities had signs of mitochondrial dysfunction. [18] Specifically, during exercise, they had decreased fat oxidation and increased lactate production at much lower exercise intensity than expected from historical controls. This suggests their mitochondria are unable to utilize oxygen effectively. However, this study did not look at ferritin or hemolobin levels.

While anemia of chronic disease is unlikely to be the only aspect of COVID creating mitochondrial dysfunction, no mitochondrion will function correctly in an environment where hemoglobin levels are inadequate to deliver oxygen to the trillions of mitochondria within the body.

Any signs of anemia – fatigue, dyspnea upon exertion, cognitive impairment, hair loss – should be followed up with complete bloodwork for anemia, and the anemia should be corrected before any more complicated hypotheses about mitochondrial dysfunction are pursued. Copper is needed for the breakdown of ferritin to release stored iron, [19] so any deficiency of copper should be corrected as part of this process if it is present. Additionally, it should be kept in mind that many other nutrient deficiencies can cause anemia. These include zinc, copper, riboflavin, iodine (and any other cause of hypothyroidism), vitamin B6, vitamin C, vitamin A, vitamin E, selenium, folate, and vitamin B12. [20]

One caveat to the interpretation of iron deficiency is that if the acute COVID illness was severe but ferritin has been ineffective at mopping up all the free iron, free iron could be elevated. It is notable that some practitioners tie iron deficiency to muscle pain, [21] while it is more often found in the literature as a side effect of iron infusion, where it usually occurs alongside joint pain. [22] If ferritin has not been able to mop up the free iron, ferritin is less likely to be elevated and the transferrin saturation is likely to be over 40%. The skin is also more likely to be more darkly pigmented, whereas skin becomes pale in iron deficiency anemia.

Zinc

Smell and taste dysfunction has a long-recognized association with zinc deficiency. A small study from the early 1980s found that patients with smell and taste dysfunction appear to have 33-44% lower than expected total-body stores of zinc, and that it takes almost a year of supplementing 100 milligrams per day as zinc sulfate to correct that. [23] Their studies focused overwhelmingly on using these individuals to study how the body stores and handles zinc, and did not comment on whether the smell and taste dysfunction could be reversed with zinc.

Clinical trials using zinc to reverse smell and taste dysfunction have had variable results. Zinc does not seem to help these disorders when due to traumatic injury or chemotherapy, but has shown improvement in patients who have clear cases of zinc deficiency. [24–28] The most successful protocol used was 25 milligrams per day zinc as zinc acetate for 6-12 weeks in hemodialysis patients. [26] Other studies showing some success used 29 mg of zinc as zinc picolinate three times a day for three months [24] or 20 milligrams per day zinc as zinc gluconate for 3 months [27] in patients with isolated zinc-associated taste and smell dysfunction.

Given how profoundly deficient the total body stores of zinc can become and how long it takes to restore them using high doses of zinc, it makes far more sense to measure zinc status and correct it if warranted than to try to copy a protocol from any of the above taste and smell dysfunction trials. More than likely, those trials would have gotten far better results if they had copied the earlier study from the 1980s that used 100 milligrams zinc per day for a year to largely restore the massive whole-body zinc deficits found in those patients.

Zinc has not been tested specifically in a large population of patients with postviral taste and smell dysfunction, but infections cause plasma zinc to fall. [29] This is probably because zinc is copiously used by the immune system for matrix metalloproteinase enzymes. These are used first to allow immune cells to infiltrate tissues and attack pathogens, and then are used liberally in the healing phase to remodel damaged tissue and lay down fresh tissue. Infections at minimum must take zinc away from other priorities through the end of the healing process, and may actually deplete body stores of zinc. Certainly, if diarrhea is present in an illness, it will cause zinc to leave the body through lost bile.

Thus, for long-COVID cases that involve smell and taste dysfunction, the immediate issue at hand is to measure plasma zinc and use zinc supplementation if necessary to raise it into the optimal range and keep it there permanently. This should be dealt with right away before considering other more difficult-to-treat hypotheses such as damage to olfactory nerves.

Besides taste and smell dysfunction, other textbook signs of zinc deficiency include diarrhea, hair loss, poor immunity including low lymphocytes, and delayed wound healing. [30] Zinc deficiency may often be seriously compromised in people before they get COVID, and the poor immunity that results may worsen the severity of the illness or the duration of longhauler symptoms. Poor healing of the lungs and the diarrhea and hair loss that are frequently noted as long-COVID symptoms could be additional signs of zinc deficiency.

Now that these two nutritional elephants are out of the room, we turn to the leading hypotheses of long-COVID and attempt to fit them into an overarching immunological paradigm centered around my paradigm of what causes COVID cases to become severe.

Toxicological and Immunological Paradigms for Long-COVID

The three leading hypotheses to explain long-COVID are microclots, persistent antigen, and immune dysfunction.

Microclots

In one study, after a median followup of two months from infection, D-dimer levels remained elevated in 25.3% of patients, even though CRP, a general marker of inflammation, and markers of the clotting cascade returned to normal in over 90% of patients. [31] D-dimer is a product of the breakdown of clots, whereas the other markers are causes of clots. This suggests that in the majority of the cases where D-dimer stays elevated for months, the clots are no longer being formed. Instead, their breakdown is lingering far longer than expected. This might reflect the fact that the virus’s spike protein makes clots more difficult to break down, leading to a very delayed clearance time for clots that form during acute illness. [32]

Consistent with this, another study found that long-COVID patients have plasma that is not any more viscous than healthy controls, yet has microclots that are resistant to breakdown. [33] By contrast, acute COVID patients have the same breakdown-resistant microclots, but also have more viscous plasma. This means the viscosity of plasma is returning to normal after acute illness, but breakdown-resistant clots are still found in long-COVID patients.

The way they show the clots are resistant to breakdown is to treat it with the enzyme trypsin. After one trypsin treatment, clots from healthy plasma are completely broken down, but these anomalous microclots from long-COVID samples are not. However, the good news is that a second trypsin treatment fully breaks them down. In other words, it is not that they can’t be broken down. It’s that it just takes twice as much enzyme to break them down within a given timeframe, or twice as long to break them down with a given amount of enzyme.

The other piece of good news is that the presence of D-dimer is in and of itself evidence that the clots are being broken down. This is because D-dimer is a breakdown product of clots.

Given that long-COVID plasma is not any more viscous than we would expect, it is not obvious that the microclots are the cause of the symptoms. Nevertheless, they could be hurting circulation in the smallest microcapillaries.

Immune Dysfunction and Antigen Persistence

When long-COVID patients with symptoms 8 months out from infection are compared to fully recovered COVID patients, the long-COVID patients are distinguished by high levels of monocytes and plasmocytoid dendritic cells – two representatives of the innate immune system – a depletion of T and B cells that have not been activated, and markers of excessive T cell activation and exhaustion.[34]

The authors of this paper concluded, “In summary, our data indicate an ongoing, sustained inflammatory response following even mild-to-moderate acute COVID-19, which is not found following prevalent coronavirus infection. The drivers of this activation require further investigation, but possibilities include persistence of antigen, autoimmunity driven by antigenic cross-reactivity or a reflection of damage repair.”

It is not obvious that the T cell exhaustion is the cause of long-term symptoms. In mice, this same phenomenon occurs after infection with the flu. If the T cell exhaustion is reversed, the mice become more resistant to a second flu infection, but this comes at the expense of greater fibrosis (scar tissue) in the lungs. [3] In other words, T cell exhaustion seems to be a compensation for the damaging effects of T cell hyperactivity, and serves to restrain further damage to the host.

The clearest demonstration of persistent antigen so far has been in a sample of irritable bowel disease (IBD) patients. [2] This was a series of 46 IBD patients who had previously tested positive for COVID and came in for an endoscopy related to their IBD. The endoscopies were, on average, 7.3 months from their positive test. 59% of the patients were in remission as far as their IBD was concerned. Although viral RNA could not be found in their stool, it was found in biopsied gut tissue in 70% of the patients. In all of the patients whose gut tissue tested positive for viral RNA, the gut tissue also tested positive for viral proteins. However, in no cases could replicable virus be found. In other words, there is no chronic infection, but there is a lingering presence of bits and pieces of the viral proteins.

Strikingly, 46% of the patients reported long-COVID symptoms and all of them showed presence of persistent viral antigen.

In trying to explain why the viral antigens persist in some but not others, they found that low levels of anti-nucleocapsid antibodies were associated with antigen persistence. They also noted that patients who used immunosuppressive drugs that block the inflammatory cytokine tumor necrosis alpha (TNF-alpha) had impaired T cell responses to the nucleocapsid protein.

Unvaccinated patients were twice as likely (47%) to test negative for persistent antigen as vaccinated patients (23%), but they buried this by separating the vaccinated patients into seven different groups based on which vaccine they took and how many doses they received, and then performed statistics on the overall comparison of 8 groups and found that it barely escaped statistical significance (P=0.08). Perhaps the vaccines bias immunity toward the spike protein and away from the nucleocapsid protein during a breakthrough infection.

While this study is small and limited to IBD patients, its finding that 100% of the long-COVID patients had fragments of viral RNA and proteins in their gut biopsies but not their stool is very supportive of the idea that these antigens persist by stealth in long-COVID patients, escaping measurement in easily obtained samples, but discovered when tissues are probed more deeply.

On the other hand, since 70% of the patients showed viral antigen persistence but only 46% reported long-COVID symptoms, this means that 35% of the people who had viral antigen persistence were symptom-free. Thus, viral antigen persistence in biopsied tissue is extremely sensitive – it picks up everyone with long-COVID according to this study – but much less specific: it identifies quite a few people who don’t have long-COVID.

Perhaps viral antigen persistence is necessary but insufficient to cause long-COVID, or perhaps it is simply a marker of something else that causes long-COVID.

For example, viral antigen persistence in the gut might indicate any of the following:

It is causing immune reactions that lead to autoimmunity or lead to persistence of inflammatory cytokines.
It is a result of immune dysfunction that leads to inappropriately sustained inflammatory cytokines or autoimmunity but poor antigen clearance.
It is a general marker of incomplete clearance of viral proteins, and thus correlates very well with the persistence of spike protein or spike protein fragments in the blood causing breakdown-resistant microclots.

The data are, as yet, insufficient to draw a definitive line of causality.

However, if these data can fit cleanly into my immunological paradigm of COVID severity, then I prefer to fit them into it to draw some tentative conclusions:

In a healthy response to infection, myeloid-derived suppressor cells (MDSCs) rise in the first day, temporarily suppressing the adaptive response while the innate response takes hold, allowing the adaptive response to learn specificity. Very soon after this, MDSCs fall, and the well-crafted adaptive response takes over.
If MDSCs do not fall in the first few days of infection, but rather continue rising through the first month, they suppress the entire antigen-specific adaptive immune response during this time. This leads to poor clearance of virus and viral antigen.
During this time the innate immune system is overactive and causes more tissue damage.
The T cells finally step in very late when the task of clearing the virus and its proteins is much greater and more overwhelming. They eventually work overtime, doing a poorer job at accomplishing a harder task. In the process, they make more of a mess than they would have if they were working efficiently and on time from the beginning. Tissue damage elicits T cell responses that are more broad than appropriate, leading to autoimmunity.
T cell exhaustion becomes an adaptive mechanism of restraining the damage to the host.
The end result is more tissue damage, more inflammatory cytokines, more antigen persistence, and autoimmunity.

The IBD paper raises the possibility that anti-inflammatories used during acute illness and during recovery could compromise antigen clearance. This is not a definitive finding, merely a possibility. However, it tentatively makes me very cautious about any drugs or herbs that are used specifically to lower inflammatory markers. I believe these should be avoided wherever they are not medically necessary, or wherever they are not needed to relieve truly debilitating symptoms.

My immunological paradigm suggests that vitamins A and D used especially in the first two days should lead to much more robust antigen clearance and a much more effective transition from the innate to adaptive immune systems, resulting in less tissue damage. It also suggests that correcting amino acid imbalances as soon as they occur in the acute phase using arginine, tryptophan, NAC, and glycine will help correct any lost opportunities with early A and D supplementation.

MDSCs can be found persisting for at least three months, [35] and vitamins A and D have much broader effects on the immune system that include synergistically suppressing autoimmunity. [36] This warrants continued use of the vitamins A and D supplementation from the acute protocol.

A plasma amino acid analysis could be used to look for low levels of arginine, tryptophan, and glycine to be taken as markers of persistent MDSC activity, which, if found, would warrant continued use of the amino acid cocktail from the acute protocol.

Providing MDSCs have been cleared, I believe that antigen persistence is a result of T cell exhaustion that has been implemented by the body to restrain tissue damage. Within this paradigm, drugs and herbs that directly manipulate the immune system should not be used. Suppressing the immune response could lead to further antigen persistence while stimulating the immune response could lead to greater tissue damage. Rather, addressing the root cause means protecting tissues from further damage and promoting their healing.

In my working model, this is the path toward relieving late-stage T cell exhaustion: make it safe for the T cells to wake up.

Protecting tissues and promoting their healing is the topic of the next section.

Long-Term Damage to the Lungs or Other Organs

Among hospitalized COVID patients, tissue damage in the lungs appears to take at least six months to heal for everyone, and to take longer than a year for many patients. The probability of taking longer than a year increases dramatically in those who received mechanical ventilation. [37] For example, at six months 100% of patients still have at least one abnormal pattern on a CT scan; at six months, this declines to 40% of patients that did not receive mechanical ventilation, but to only 87% in those that did.

Whether mechanical ventilation caused the lasting lung damage or whether the severity of the initial illness that led the doctors to use the mechanical ventilation was the culprit is unclear. However, the point is that healing of tissue damage is still taking place beyond the six-month mark in the worst cases, and in a large minority of less severe cases.

The damage is first and foremost laid down by the viral toxins, which poke holes in membranes, thereby creating extremely broad dysfunction in virtually every cellular system.

This also mimics the inflammatory process, where cytokines cause influxes of calcium into cells that then activate nitric oxide to mediate such processes as vasodilation and the permeability of endothelial and epithelial barriers. This is a necessary part of inflammation that allows immune cells to penetrate tissues, but in excess leads to such problems as edema, pulmonary hypertension, and multisystem inflammatory syndrome.

The second layer of damage is driven by MDSCs using oxidants and glycating factors to suppress T cells, and mature cells of the innate immune system using excessive reliance on the oxidative burst. This leads to production of methylglyoxal, nitric oxide, superoxide, peroxynitrite, hydrogen peroxide, and hypochlorous acid (bleach).

A third layer of damage may be a late response of T cells. When the virus has replicated too much, there are too many infected cells to be killed. If tissue damage has proliferated, T cells might mount responses to host antigens, resulting in autoimmunity.

The chief defense against spike protein accumulating in cellular membranes is a robust immune system following its proper rhythm, followed by anything that can help minimize the replication of the virus, such as antimicrobial flushes. Low replication and clearance of infected cells is the recipe for being spike protein-free. My protocol is designed to do exactly that during acute illness.

The chief defense against spike protein mimicking the inflammatory process as well as the glycation and oxidative stress caused by the MDSCs and innate immune cells is glutathione. Glutathione sequesters nitric oxide, preventing it from causing excessive vasodilation or hyperpermeability, and preventing it from joining with superoxide to make peroxynitrite. Zinc, copper, and manganese are needed to clear superoxide to hydrogen peroxide, while selenium, iron, and glutathione are needed to convert hydrogen peroxide to water. The clearance of hydrogen peroxide prevents it from combining with chloride to make bleach.

The use of glutathione and these nutrients should not bee seen as a drug-like approach with the aim to decrease the production of oxidants. Rather, these things need to be adequately supplied so the immune cells can produce the right amount of oxidants needed to kill pathogens, while they and the cells of the surrounding tissue protect themselves from damage.

If these steps are followed, they should preempt the third layer of damage. Robust clearance of the virus prevents the job of T cells from becoming too large. Prevention of tissue damage prevents the stimulus for autoimmunity.

Nevertheless, some level of tissue damage will be done, and if someone is six months into the healing process, the prevention part is over. After the first few weeks of illness, the process of healing becomes dominant.

Healing lung tissue after a respiratory infection involves the following processes: [3]

Cellular differentiation is needed to lay down new epithelial cells to line the lungs. Epithelial cell differentiation is overwhelmingly dependent on vitamin A.
The remodeling is largely performed by macrophages. Differentiation of macrophages is dependent on vitamin D.
Matrix metalloproteinase enzymes are used to remodel the tissue. These enzymes are dependent on zinc.
Fresh collagen must be laid down. Collagen synthesis can be stimulated with gelatin or collagen peptides, and is dependent on vitamin C and copper.
Fresh extracellular matrix must be laid down. In addition to collagen, this is rich in sulfur-containing combinations of protein and carbohydrate that are synthesized using manganese.

From among these nutrients, those that are actually incorporated as major components of the tissue (collagen, sulfur) and those that are used as signaling molecules (vitamins A and D) are the ones that are most likely needed above and beyond otherwise optimal intakes. Eating a diet on the upper range of a healthy protein intake (1 gram per pound bodyweight or 2.2 grams per kilogram bodyweight) will ensure plenty of sulfur, as long as iron, vitamin B6, and molybdenum levels levels are adequate to harvest the sulfur. The protein will ensure high intakes of most other amino acids that could be used in healing as well, such as glutamine.

Other Models of Long-COVID

Multisystem inflammatory syndrome can occur after acute COVID and presents with a continuing fever in almost everyone, and in the majority of cases also includes low blood pressure, cardiac dysfunction, shortness of breath, and diarrhea. [38] This is probably driven by epithelial barrier dysfunction [39] as a result of nitric oxide binding to the proteins that make up the junctions between cells and causing the junctions to withdraw. [40–44]

Glutathione prevents nitric oxide from binding to these proteins in the first place, [45] while the selenium-dependent protein thioredoxin removes it from them after it has bound. [46] In addition, blue, green, and ultraviolet light remove nitric oxide from these proteins. [45,47] Liberal exposure of the naked skin to daytime, outdoor, unprotected sunlight with careful attention to avoid sunburn may prove valuable for reversing this, while internally nourishing glutathione and thioredoxin should provide the bulk of the benefit.

Acetylcholine is a neurotransmitter that plays an important role in both taste and smell and in cognitive function. Cognitive impairment is often treated with acetylcholinesterase inhibitors, drugs that prevent the breakdown of acetylcholine. In a study unrelated to COVID, among patients with mild cognitive impairment, the ability of an anticholinergic nasal spray to hurt a person’s sense of smell was used to identify people whose cognitive function improved the most with acetylcholinesterase inhibitors. [48] Hypothetically, strategies around boosting acetylcholine may be helpful in cases of cognitive impairment or smell and taste dysfunction that do not respond to the correction of iron and zinc status.

My COVID protocol includes strategies for prevention, for use at the onset of illness, for use if the illness becomes severe, as well as a healing diet and a long-COVID protocol. It can be accessed here:

The COVID Guide

References can be found below.

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References

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